Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States. CLL involves the cancerous proliferation of lymphocytes. It is most common among older adults; 90 percent of the cases are in people more than 50 years old. It occurs 1–3 times more often among men than among women. The onset of CLL tends to be insidious, with symptoms developing gradually. Because it involves an overproduction of mature, functional lymphocytes, persons with this disorder may survive for years. In contrast, in some, the disorder proceeds very rapidly, and requires immediate treatment. Currently, the adenine deoxynucleosides fludarabine (fludara) and 2-chlorodeoxyadenosine (2CdA) are the drugs of choice to treat the disease. However, clinical remissions are seldom induced, and patients eventually succumb from their leukemia.
Multiple myeloma is a cancer in which malignant plasma cells accumulate in the bone marrow and produce an immunoglobulin, usually monoclonal IgG or IgA. Common complications of overt multiple myeloma include recurrent bacterial infections, anemia, osteolytic lesions, and renal insufficiency. Multiple myeloma is responsible for about 1 percent of all cancer-related deaths in Western countries. Its epidemiologic pattern remains obscure, and its cause is unknown. D. A. Reidel et al., Hematol. Oncol, Clin. North Am., 6, 225 (1992).
Melphalan, cyclophosphamide, and glucocorticoids are the most effective drugs against multiple myeloma; the classic combination of melphalan and prednisone is still the standard treatment for most patients. R. Alexanian et al., N. Engl. J. Med., 330, 484 (1994). Combinations of other drugs, including vinca alkaloids, nitrosoureas, and anthracyclines, are active against myeloma but are no more effective than melphalan and prednisone. R. Alexanian et al., N. Engl. J. Med, 330, 484 (1994). Results with novel agents like purine analogues or taxane derivatives have not been promising. The regimen of vincristine, doxorubucin, and dexamethasone (VAD)—or a similar combination, with high-dose methylprednisolone substituted for high-dose dexamethasone (VAMP)—which is often used in patients with newly diagnosed disease, has not prolonged survival more than other regimens in a randomized clinical trial; its main advantage is the rapid induction of remission. R. Alexanian et al., N. Engl. J. Med., 330, 484 (1994).
The lack of progress with conventional chemotherapy has heightened interest in high-dose therapy. Treatment with melphalan in high doses (140 mg per square meter of body-surface area, given intravenously without hematopoietic support) can induce complete remissions in 20 to 30 percent of patients (including disappearance of the M component), but it causes severe and sometimes irreversible myelosuppression. The rate of death due to the toxicity of this treatment is approximately 10 percent in patients with newly diagnosed disease and more than 20 percent in previously treated patients. D. Cunningham et al., J. Clin. Oncol, 12, 764 (1994); J. L. Harcovseau et al., Blood, 79, 2827 (1992); B. Barlogle et al., Blood, 22, 2015 (1988).
Transplantation of autologous hematopoietic stem cells (obtained from bone marrow or blood) accelerates the restoration of hematopoiesis after the administration of high dose melphalan and allows for a combination of intensive chemotherapy and total-body irradiation or for the use of higher doses of melphalan (200 mg per square meter). Autologous stem-cell transplantation may be a useful form of salvage therapy for patients whose disease is refractory to initial standard chemotherapy and for patients in relapse with chemosensitive myeloma, but it has limited value for patients in relapse with resistant myeloma. Other therapies for multiple myeloma are discussed in R. Bataille et al., N. Engl. J. Med, 336, 1657 (1997).
The number of nonsteroidal anti-inflammatory drugs (NSAIDs) has increased to the point where they warrant separate classification. In addition to aspirin, the NSAIDs available in the U.S. include meclofenamate sodium, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac and tolmetin for the treatment of arthritis; mefenamic acid and zomepirac for analgesia; and ibuprofen, fenoprofen and naproxen for both analgesia and arthritis. Ibuprofen, mefenamic acid and naproxen are used also for the management of dysmenorrhea.
The clinical usefulness of NSAIDs is restricted by a number of adverse effects. Phenylbutazone has been implicated in hepatic necrosis and granulomatous hepatitis; and sulindac, indomethacin, ibuprofen and naproxen with hepatitis and cholestatic hepatitis. Transient increases in serum aminotransferases, especially alanine aminotransferase, have been reported. All of these drugs, including aspirin, inhibit cyclooxygenase, that in turn inhibits synthesis of prostaglandins, which help regulate glomerular filtration and renal sodium and water excretion. Thus, the NSAIDs can cause fluid retention and decrease sodium excretion, followed by hyperkalemia, oliguria and anuria. Moreover, all of these drugs can cause peptic ulceration. See, Remington's Pharmaceutical Sciences, Mack Pub. Co., Easton, Pa. (18th ed., 1990) at pages 1115–1122.
There is a large amount of literature on the effect of NSAIDs on cancer, particularly colon cancer. For example, see H. A. Weiss et al., Scand J. Gastroent., 31, 137 (1996) (suppl. 220) and Shiffet al., Exp. Cell Res., 222, 179 (1996). More recently, B. Bellosillo et al., Blood, 92, 1406 (1998) reported that aspirin and salicylate reduced the viability of B-cell CLL cells in vitro, but that indomethacin, ketoralac and NS-398, did not.
C. P. Duffy et al., Eur. J. Cancer, 34, 1250 (1998), reported that the cytotoxicity of certain chemotherapeutic drugs was enhanced when they were combined with certain non-steroidal anti-inflammatory agents. The effects observed against human lung cancer cells and human leukemia cells were highly specific and not predictable; i.e., some combinations of NSAID and agent were effective and some were not. The only conclusion drawn was that the effect was not due to the cyclooxygenase inhibitory activity of the NSAID.
The Duffy group filed a PCT application (WO98/18490) on Oct. 24, 1997, directed to a combination of a “substrate for MRP”, which can be an anti-cancer drug, and a NSAID that increases the potency of the anti-cancer drug. NSAIDs recited by the claims are acemetacin, indomethacin, sulindac, sulindac sulfide, sulindac sulfone, tolmetin and zomepirac. Naproxen and piroxicam were reported to be inactive.
Nardella et al. (PCT/WO/00/02555) disclose that the level of leukemic lymphocytes in patients suffering from chronic lymphocytic leukemia (CLL) is reduced by the administration of the NSAID etodolac. See also, F. A. Nardella et al., Arthritis and Rheumatism, 42, S56 Abstract 41 (September 1999).
Therefore, a continuing need exists for methods to control cancers, such as leukemias, and to increase the potency of anti-cancer drugs with relatively non-toxic agents.